Current Trends in Atypical Diabetes

The term “diabetes” now encompasses forms that don't fit neatly into the type 1 or type 2 categories––these diabetes types are termed as "atypical diabetes." These atypical forms have enhanced our knowledge of insulin dynamics and islet autoimmunity – suggesting the need for classification based on specific endotypes. 

Atypical diabetes can account for 5-11% of cases and includes monogenic types like maturity-onset diabetes of the young (MODY) and neonatal diabetes – caused by single-gene variants affecting β-cell function. GCK-MODY leads to mild hyperglycemia without the need for treatment, while HNF1A-MODY can be managed with sulfonylureas. 

Oligogenic diabetes involves multiple gene variants, while syndromic diabetes, such as Wolfram syndrome, involves broader multiorgan dysfunction. 

Mitochondrial diabetes results from dysfunction of the mitochondria – affecting energy-demanding tissues. Recognizing these endotypes enables more accurate diagnosis and tailored treatments, improving patient outcomes.  

Lipodystrophic diabetes is marked by loss of body fat, either generally or partially. This leads to increased musculature, severe hypertriglyceridemia, and hepatomegaly due to steatohepatitis. The insulin resistance in these patients causes hyperglycemia and severe acanthosis nigricans. Studies on lipodystrophic syndromes highlight the role of adipose tissue in metabolism and insulin sensitivity. Hormones like leptin and adiponectin regulate satiety, glucose, and fat metabolism, preventing obesity-related complications. Treatments vary based on the lipodystrophy type, ranging from metformin and insulin to FDA-approved metreleptin. 

Other forms of atypical diabetes include progeroid syndromes, familial partial lipodystrophy, and acquired generalized lipodystrophy.

Source: Stone SI, Balasubramanyam A, Posey JE. Diabetes Care. 2024 May 1;47(5):770-81.